Smoking is responsible for over 400,000 premature deaths and $50 Billion of medical costs in the USA each year. An estimated 70% of smokers want to quit, however only 2.5% succeed in quitting each year. Nicotine is believed to be the main reinforcing and addicting component in tobacco smoke, however the rewarding mechanism of nicotine is poorly understood. A greater understanding of nicotine's effects within the brain will identify novel targets for smoking cessation therapies. Electrophysiological studies have implicated both the B2- and a7-containing nicotinic acetylcholine receptors (nAChRs) in nicotine-induced release of dopamine (DA) within the mesolimbic DA system. This release of DA is thought to be critical for nicotine reinforcement, however the contributions of the beta2 and alpha nAChR subunits have not been examined in a behavioral model of nicotine reward. Toward this end, I propose self-administration studies using beta2 and alpha7 nAChR subunit knockout and transgenic mice to determine their respective contributions to nicotine reward. In addition, I will study whether nicotine alters cocaine- and amphetamine-regulated transcript (CART) expression, a neuropeptide with high levels of expression in the nucleus accumbens and hypothalamus. CART expression is increased with cocaine or amphetamine administration. CART has been shown to have reinforcing properties, to decrease food intake, and to induce anxiety. CART knockout mice will also undergo nicotine self-administration experiments to determine if CART is necessary for nicotine reinforcement.